Substituted phenylcyclohexane carboxylic acid amides and their use as adenosine uptake inhibitors

ABSTRACT

The present invention relates to substituted phenylcyclohexanecaboxamides of the formula (I), to processes for their preparation and to their use in medicaments, in particular for treating cardiovascular disorders.

The present invention relates to substitutedphenylcyclohexanecarboxamides, to a process for their preparation and totheir use in medicaments, in particular for treating cardiovasculardisorders, for example for the acute and chronic treatment of ischaemicdisorders.

Adenosine is an endogenic effector with cell-protective activity, inparticular under cell-damaging conditions with limited oxygen supply,such as, for example, in ischaemia. Adenosine is a highly effectivevasodilator. It increases ischaemic “preconditioning” (R. Strasser, A.Vogt, W. Scharper, Z. Kardiologie 85, 1996, 79-89) and can promote thegrowth of collateral vessels. It is released under hypoxic conditions,for example in the case of cardiac or peripheral occlusive diseases (W.Makarewicz “Purine and Pyrimidine Metabolism in Man”, Plenum Press NewYork, 11, 1998, 351-357). Accordingly, adenosine protects against theeffects of disorders caused by ischaemia, for example by increasing thecoronary or peripheral circulation by vasodilation, by inhibitingplatelet aggregation and by stimulating angiogenesis. Compared tosystemically administered adenosine, the adenosine-uptake inhibitorshave the advantage of selectivity for ischaemia. Systemicallyadministered adenosine causes a strong general, but frequentlyundesired, lowering of the blood pressure. The adenosine-uptakeinhibitor increases the effect of the adenosine which is formed locallyowing to the ischaemia and thus only dilates the vessels in theischaemic regions. Here, too, adenosine-uptake inhibitors increase theeffects of adenosine and can be administered orally or intravenously forthe prevention and therapy of ischaemic disorders, for example ofcoronary heart disease, of stable and unstable angina pectoris, ofperipheral and arterial occlusive diseases, of thrombotic vascularocclusion, myocardial infarction and reperfusion damage. Moreover, owingto their potential to increase angiogenesis, they are particularlysuitable for a permanent therapy of all occlusive diseases.

Adenosine-uptake inhibitors can also be used for potentiating the effectof nucleobase, nucleoside or nucleotide antimetabolites in thechemotherapeutical treatment of cancer and in antiviral (for exampleHIV) chemotherapy.

EP-A0 611 767 and EP-A-725 064 disclose phenylcyclohexylcarboxamideswhich can be used for the treatment of atherosclerosis or restenosis.

The present invention relates to compounds of the general formula (I)

in which

-   A, D, E and G are identical or different and represent CH groups or    nitrogen atoms,-   L¹ and L² are identical or different and independently of one    another each represents one or more radicals selected from the group    consisting of hydrogen, halogen, hydroxyl, carbxyl, cyano, nitro,    trifluoromethyl, trifluoromethoxy, (C₁-C₄) -alkyl, (C₁-C₆)-alkoxy or    (C₁-C₆)-alkoxycarbonyl,-   R¹ represents the CH₂—OH group, or    -   represents a radical of the formula CO—NR R⁵,    -   in which    -   R⁴ and R⁵ are identical or different and each represents        hydrogen or (C₁-C₆) -alkyl,-   R² represents (C₃-C₈)-cycloalkyl,    -   represents (C₁-C₈)-alkyl which is optionally interrupted by an        oxygen or sulphur atom or by a radical NR⁶    -   represents a 4- to 8-membered saturated heterocycle which is        attached to the imidazole ring via a nitrogen atom and which        optionally contains a further oxygen or sulphur atom, or    -   represents a 4- to 8-membered saturated heterocycle which        contains a radical of the formula NR⁷ and optionally        additionally one nitrogen, oxygen or sulphur atom,    -   where (C₃-C₈)cycloalkyl, (C₁-C₈)alkyl which is optionally        interrupted by an oxygen or sulphur atom, the 4- to 8-membered        saturated heterocycle which is attached to the imidazole ring        via a nitrogen atom and which optionally contains a further        oxygen or sulphur atom and optionally (C₁-C₈)-alkyl which is        interrupted by a radical NR⁶ and optionally the 4- to 8-membered        saturated heterocycle which contains a radical of the formula        NR⁷ and optionally additionally one nitrogen, oxygen or sulphur        atom are substituted by one to three hydroxyl groups and/or by a        radical of the formula —NR⁸R⁹    -   in which    -   R⁶ and R⁷ are identical or different and each represents        hydrogen, (C₁-C₄) alkyl, hydroxy-(C₁-C₆)-alkyl or        (C₃-C₇)Cycloalkyl,    -   R⁸ and R⁹ are identical or different and each represents        hydrogen, (C₁-C₆) alkyl or (C₃-C₇)-cycloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom form a 4- to        8-membered saturated heterocycle which may optionally        additionally contain one oxygen or sulphur atom or a radical of        the formula NR¹⁰,        -   in which        -   R¹⁰ represents hydrogen, (C₁-C₆)alkyl or (C₃-C₇)-cycloalkyl,-   and-   R³ represents a phenyl, naphthyl, pyrimidinyl, pyridyl, furyl or    thienyl ring, where the rings are optionally mono- or    polysubstituted by radicals selected from the group consisting of    halogen, hydroxyl, carboxyl, cyano, nitro, trifluoromethyl,    trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)alkoxy and    (C₁-C₆)-alkoxycarbonyl,-   and their enantiomers and diastereomers and their respective salts,    hydrates and, if appropriate, their prodrugs.

Among these, preference is given to compounds of the general formula (I)having the stereochemistry of the general formula (Ia) below

where the substituents R¹, R², R³, L¹ and L² and the radicals A, D, Eand G are as defined above.

Physiologically acceptable salts of the compounds according to theinvention can be salts of the substances according to the invention withmineral acids, carboxylic acids or sulphonic acids. Particularpreference is given, for example, to salts with hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonicacid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonicacid, naphthalenedisulphonic acid, acetic acid, propionic acid, lacticacid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoicacid.

Depending on the substitution pattern, the compounds according to theinvention can exist in stereoisomeric forms which either are like imageand mirror image (enantiomers) or are not like image and mirror image(diastereomers). The invention relates both to the enantiomers ordiasteromers and to their respective mixtures. The racemic forms, likethe diastereomers, can be separated in a known manner into thestereoisomerically uniform components.

According to the invention “hydrates” refer to those forms of thecompounds of the above general formula (I) which, in the solid or liquidstate, form a molecular compound (solvate) by hydration with water. Inthe hydrates the water molecules are added via secondary valence bondseffected by intermolecular forces—in particular hydrogen bridge bonds.Solid hydrates contain water in the form of so-called water ofcrystallization in stoichiometric ratios, although the bonding states ofthe water molecules do not necessarily have to be the same. Examples ofhydrates are sesquihydrates, monohydrates, dihydrates or trihydrates.Possible hydrates can also be those of salts of the compounds accordingto the invention.

According to the invention, “prodrugs” are forms of the compounds of thegeneral formula (I) or (Ia) above, which for their part can bebiologically active or inactive, but which can be converted into thecorresponding biologically active form (for example metabolically,solvolytically or in another way).

Examples of such “prodrugs” are, for example in the case that the aboveradical R² represents (C₃-C₈)-cycloalkyl, (C₁-C₈)-alkyl or a 4- to8-membered saturated heterocycle, in each case substituted by one ormore hydroxyl groups, compounds which can generate this/these hydroxylgroup(s) metabolically, solvolytically or in another manner, for exampleesters, in particular amino acid esters (for example glycine esters,β-alanine esters, N-aminoethylglycine esters, etc.), phosphates,acetals, semiacetals, glucuronates, and the like.

(C₁C₈)-alkyl, (C₁-C₆)-alkyl etc., represent a straight-chain or branchedalkyl radical having 1 to 8 or 1 to 6 carbon atoms. Examples which maybe mentioned are: methyl, ethyl, n-propyl, isopropyl, tert-butyl,n-pentyl and n-hexyl. Preference is given to a straight-chain orbranched alkyl radical having 1 to 4 carbon atoms (C₁-C₄). Particularpreference is given to a straight-chain or branched alkyl radical having1 to 3 carbon atoms (C₁-C₃).

(C₁-C₈)-alkyl, (C₁-C₈)-alkyl etc., which is interrupted by an oxygen orsulphur atom and which is substituted by one to three hydroxyl groupsand/or by a radical of the formula —NR⁸R⁹ represent, for example,1,3-dihydroxy-prop-2-oxy-methyl, 2-hydroxy-ethoxy-methyl,2-hydroxy-prop-1-oxy-methyl, 3-hydroxy-prop-1-oxy-methyl,morpholin-4-yl-methyl, piperidin-1-yl-methyl, 2-amino-ethyl,2-dimethylamino-ethyl or diethylamino-methyl.

(C₁-C₈)-alkyl, (C₁-C₆)-alkyl etc., which is interrupted by a radical NR⁶and which is optionally substituted by one to three hydroxyl groupsand/or by a radical of the formula —NR⁸R⁹ represent, for example,N-(2-hydroxy-ethyl)-aminomethyl, N-(2-hydroxyethyl)-N-methyl-aminomethylor N,N-bis-(2-hydroxy-ethyl)-aminomethyl.

Hydroxy-(C₁-C₆)-alkyl or hydroxy-(C₁-C₄)alkyl represents astraight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbonatoms. Examples which may be mentioned are: hydroxymethyl,2-hydroxy-ethyl, 2-hydroxy-prop-1-yl, 3-hydroxy-prop-1-yl,3-hydroxy-prop-2-yl, 2-hydroxy-but-1-yl, 5-hydroxy-pent-1-yl and6-hydroxy-hex-1-yl. Preference is given to 2-hydroxy-ethyl.

(C₁-C₆)-Alkoxy represents a straight-chain or branched alkoxy radicalhaving 1 to 6 carbon atoms. Examples which may be mentioned are:methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy andn-hexoxy. Preference is given to a straight-chain or branched alkoxyradical having 1 to 4 carbon atoms (C₁-C₄). Particular preference isgiven to a straight-chain or branched alkoxy radical having 1 to 3carbon atoms (C₁-C₃).

(C₁-C₆)-Alkoxycarbonyl represents a straight-chain or branchedalkoxycarbonyl radical having 1 to 6 carbon atoms. Examples which may bementioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl. Preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms (C₁-C₄). Particular preference is given to a straight-chain orbranched alkoxycarbonyl radical having 1 to 3 carbon atoms (C₁-C₃).

(C₃-C₈)Cycloalkyl, (C₃-C₇)-cycloalkyl etc., represent, in the context ofthe invention, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl. Cyclopropyl, cyclopentyl and cyclohexyl maybe mentioned as being preferred.

Halogen in the context of the invention generally represents fluorine,chlorine, bromine and iodine. Preference is given to fluorine, chlorineand bromine. Particular preference is given to fluorine and chlorine.

In the context of the invention, a 4- to 8-membered (preferably 5- to7-membered) saturated heterocycle which is attached via a nitrogen atomand which optionally contains a further oxygen or sulphur atomrepresents, for example, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, thiomorpholin-4-yl or 1H-hexahydroazepin-1-yl.

In the context of the invention, a 4 to 8-membered (preferably 5- to7-membered) saturated heterocycle which contains a radical of theformula NR⁷ and optionally additionally one nitrogen, oxygen or sulphuratom represents, for example, pyrrolidin-2-yl, 1-methylpyrrolidin-2-yl,pyrrolidin-3-yl, pyrazolidinl-yl, piperidin-2-yl,1-isopropyl-piperidin-3-yl, morpholin-2-yl, 4-cyclohexyl-piperazin-1-yl,thiomorpholin-3-yl, 1-ethyl-1H-hexahydroazepin-3-yl or4-methyl-1H-hexahydro-1,4 diazepin-1-yl. This heterocycle can beattached to the imidazole ring via a ring carbon atom or a ring nitrogenatom.

The compounds according to the invention can be present in eightdifferent configurations, and preference is given to the four differentconfigurations (A) to (D) below:

Very particular preference is given to the configuration (D).

Preference is also given to compounds of the general formula (I) inwhich R¹ represents a radical of the formula CO—NR⁴R⁵ where R⁴ and R⁵have the meaning given above and the other radicals are as definedabove.

Particular preference is given to compounds of the general formula (I)according to the invention

-   where-   A, D, E and G each represent the CH group,-   or one of the radicals A, D, E and G represents a nitrogen atom and    the others each represent the CH group,-   L¹ and L² are identical or different and independently of one    another each represents one or more radicals selected from the group    consisting of hydrogen, fluorine, chlorine, cyano, trifluoromethyl    and trifluoromethoxy,-   R¹ represents the —CH₂OH group, or    -   represents a radical of the formula —CO—NR⁴R⁵,    -   in which    -   R⁴ and R⁵ are identical or different and each represents        hydrogen or (C₁-C₃>alky,-   R² represents (C₃-C₇)-cloalkyl,    -   represents (C₁-C₆)alkyl which is optionally interrupted by an        oxygen or sulphur atom or by a radical NR⁶,    -   represents a 5- to 7-membered saturated heterocycle which is        attached to the imidazole ring via a nitrogen atom and which        optionally contains a further oxygen or sulphur atom, or    -   represents a 5- to 7-membered saturated heterocycle which        contains a radical of the formula NR⁷ and optionally        additionally one nitrogen, oxygen or sulphur atom,-   where (C₃-C₇)-cycloalkyl, (C₁-C₆)-alkyl which is optionally    interrupted by an oxygen or sulphur atom, the 5- to 7-membered    saturated heterocycle which is attached to the imidazole ring via a    nitrogen atom and which optionally contains one further oxygen or    sulphur atom and optionally (C₁-C₆)alkyl which is interrupted by a    radical NR⁶ and optionally the 5- to 7-membered saturated    heterocycle which contains a radical of the formula NR⁷ and    optionally additionally one nitrogen, oxygen or sulphur atom are    substituted by one hydroxyl group and/or by a radical of the formula    —NR⁸R⁹,-   in which-   R⁶ and R⁷ are identical or different and each represents hydrogen,    (C₁-C₄)alkyl, hydroxy-(C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl,-   R⁸ and R⁹ are identical or different and each represents hydrogen,    (C₁-C₄) alkyl or (C₃-C₆)-cycloalkyl,-   or-   R⁸ and R⁹ together with the nitrogen atom form a 5- to 7-membered    saturated heterocycle which may optionally additionally contain one    oxygen or sulphur atom or a radical of the formula NR¹⁰,    -   in which    -   R¹⁰ represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cloalkyl,-   and-   R³ represents a phenyl, pyridyl or thienyl ring which is optionally    mono- or polysubstituted by radicals selected from the group    consisting of fluorine, chlorine, cyano, trifluoromethyl and    trifluoromethoxy,-   and to their enantiomers and diastereomers and their respective    salts, hydrates and, if appropriate, their prodrugs.

Very particular preference is given to compounds of the general formula(I) where

-   A, D and E each represent the CH group,-   G represents a nitrogen atom or represents the CH group,-   L¹ and L² each represent hydrogen,-   R¹ represents a radical of the formula CO—NR⁴R⁵,    -   in which    -   R⁴ and R⁵ each represent hydrogen,-   R² represents (C₁-C₄)-alkyl which is optionally interrupted by an    oxygen atom, or represents a 4-R⁷-piperazin-1-yl radical    -   where (C₁-C₄)-alkyl, which is optionally interrupted by an        oxygen atom, is substituted by a hydroxyl group or by a radical        of the formula —NR⁸R⁹,    -   in which    -   R⁷ represents hydrogen, (C₁-C₄)-alkyl or (C₃C₆)-cycloalkyl,    -   R⁸ and R⁹ are identical or different and each represents        hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cloalkyl,    -   or    -   R⁸ and R⁹ together with the nitrogen atom form a morpholine        radical,-   and-   R³ represents a phenyl or pyridyl radical which may optionally be    mono- or polysubstituted by fluorine,-   and to their enantiomers and diastereomers and their respective    salts, hydrates and, if appropriate, their prodrugs.

Very particular preference is also given to compounds of the generalformula (Ib) below

-   in which-   R¹ represents a group —C(O)—NH₂,-   R² represents (C₁-C₃)-alkyl which is substituted at the terminal C    atom by a hydroxyl group,-   R³ represents a phenyl ring which is optionally substituted in the    para position by fluorine,    -   or    -   represents a pyridyl radical,-   and to their diastereomers and their respective salts, hydrates and,    if appropriate, their prodrugs.

Very particular preference is also given to the compounds of the generalformula (I) with the following structures:

and to their salts, hydrates and, if appropriate, their prodrugs.

Among these, very particular preference is given to(S)-N-{[1R2R)-2-{4-{[2-(3-hydroxypropyl)-1H-benzimidazol-1-yl]methyl}phenyl}-cyclohex-1-yl]cabonyl}-(4-fluorophenyl)glycinamide:

and to its salts, hydrates and, if appropriate, its prodrugs.

Moreover, processes for preparing the compounds of the general formula(I) according to the invention have been found where:[A] compounds of the general formula (II)

-   in which-   L² is as defined above,-   T represents (C₁-C₄)-alkyl, preferably methyl or tert-butyl,-   and-   V represents a suitable leaving group, such as, for example,    halogen, mesylate or tosylate, preferably bromine,-   are initially converted by reaction with compounds of the general    formula (III)-   in which-   A, D, E, G and L¹ are each as defined above-   and-   R¹¹ has the meaning of R² given above, where amino and hydroxyl    functions are optionally blocked by suitable amino- or    hydroxyl-protective groups,-   in inert solvents, depending on the definition of R¹¹ optionally in    the presence of a base, into the compounds of the general formula    (IV)-   in which-   R¹¹, A, D, E, G, L¹, L² and T are each as defined above,-   which are converted in a subsequent step using acids or bases into    the corresponding carboxylic acids of the general formula (V)-   in which-   R¹¹, A, D, E, G, L¹ and L² are each as defined above,-   which are, if appropriate, activated, in particular by conversion    into a corresponding carboxylic acid derivative, such as carbonyl    halide, carboxylic anhydride or carboxylic ester,-   and which are subsequently reacted by known methods with compounds    of the general formula (VI) or salts thereof-   in which-   R¹ and R³ are each as defined above-   in inert solvents,-   and, if R¹ carries one of the abovementioned protective groups, this    is optionally removed by customary methods either in the hydrolysis    to the acids (IV)→(V) or after reaction with the compounds of the    general formula (VI),-   or-   [B] if R² represents a saturated heterocycle which is attached    directly to the imidazole ring via a nitrogen atom,-   the abovementioned compounds of the general formula (II) are    initially converted with compounds of the general formula (IIIa)-   in which-   A, D, E, G and L¹ are each as defined above-   and-   Y represents halogen or mesylate, preferably chlorine, bromine or    mesylate,-   in inert solvents into the corresponding compounds of the formula    (VI)-   in which-   Y, A, D, E, G, L¹, L² and T are each as defined above,-   which are reacted in a subsequent step with compounds of the general    formula (VII)    HNR¹²R¹³  (VIII),-   in which-   R¹² and R¹³ together with the nitrogen atom form a heterocycle    according to the definition of R²-   to give compounds of the general formula (IX)-   in which-   A, D, E, G, L¹, L², R¹², R¹³ and T are each as defined above,-   which are, in the subsequent steps, converted as described under [A]    by hydrolysis into the corresponding carboxylic acids of the general    formula (X)-   in which-   A, D, E, G, L¹, L², R¹² and R¹³ are each as defined above-   and these compounds are finally reacted with the compounds of the    general formula (VI) according to known methods customary for    preparing amides from carboxylic acids and amines (for example, if    appropriate, after an activation has been carried out, in particular    by conversion into a corresponding activated carboxylic acid    derivative, such as carbonyl halide, carboxylic anhydride or    carboxylic ester) to give the compounds of the general formula (I).

The compounds of the general formula (I) obtained according to processvariant [A] or [B] can subsequently, if appropriate, be converted intothe corresponding salts by reaction with, for example, an acid.

The compounds of the corresponding diastereomeric and enantiomeric formsare prepared correspondingly, either using enantiomerically ordiastereomerically pure starting materials or by separating theracemates formed afterwards using customary methods (for exampleresolution of racemates, chromatography over chiral columns and thelike).

Thus, it is possible to prepare, for example, the compounds of thepreferred configuration of the general formula (Ia)

-   where the substituents R¹, R², R³, L¹ and L² and the radicals A, D,    E and G are as defined above-   by using, instead of the racemic compound of the general formula    (VI), the enantiomerically pure compound of the general formula (VI    a)-   or salts thereof

A very particularly preferred compound of the general formula (VI a) is(S)-(4)-fluorophenyl)glycinamide

-   and its salts (for example the hydrochloride).

A compound of the general formula (VI a) which is likewise veryparticularly preferred is (S)-(3)-pyridyl)glycinamide and its salts.

The processes according to the invention can be illustrated in anexemplary manner by the following formula schemes:

Suitable amino protective groups in the context of the invention are thecustomary amino protective groups used in peptide chemistry.

These preferably include: benzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl allyl-oxycarbonyl vinyloxycarbonyl,2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyl-oxycarbonylcyclohexoxycarbonyl, 1,1-dimethylethoxycarbonyl, adamantylcarbonyl,phthaloyl, 2,2,2-trichloroethoxycarbonyl2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl,phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl,formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl,2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl orbenzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl. Apreferred protective group for primary amines is phthalimide. Preferredprotective groups for secondary amines are benzyloxycarbonyl andtert-butoxycarbonyl.

The amino protective groups are removed in a manner known per se, forexample under hydrogenolytic, acidic or basic conditions, preferablyusing acids, such as, for example, hydrochloric acid or trifluoroaceticacid, in inert solvents, such as ether, dioxane and methylene chloride.

A suitable hydroxyl protective group in the context of the definitiongiven above is generally a protective group from the series:trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl, dimethylhexylsilyltrimethylsilylethoxycarbonyl, benzyl, triphenylmethyl (trityl),monomethoxytrityl (MMTr), dimethyloxytrityl (DMTr), benzyloxycarbonyl,2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, 4-methoxybenzyl,4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl,2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyl,2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl,methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]-methyl,2-methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl, benzoyl,N-succinimide, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl,4-chlorobenzoyl or 4-methoxybenzoyl. Preference is given totert-butyldimethylsilyl.

The hydroxyl-protective group is removed in a manner known per se, forexample using acid or base, or by addition of tetrabutylammoniumfluoride, or is carried out during the hydrolysis of the carboxylicacid.

Suitable solvents for the processes are customary organic solvents whichdo not change under the reaction conditions. These include ethers, suchas diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, orhydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane ormineral oil fractions, or halogenated hydrocarbons, such asdichloromethane, trichloromethane, tetrachloromethane, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, pyridine, dimethylsulphoxide, dimethylformamide, N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane. It isalso possible to use mixtures of the solvents mentioned. For the process[A] (II)+(III)→(IV), preference is given to diethyl ether,tetrahydrofuran and dimethylformamide. Particular preference is given todimethylformamide.

Suitable for use as bases in the process according to the invention are,in general, inorganic or organic bases. These preferably include alkalihydroxides, such as, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides, such as, for example, bariumhydroxide, alkali metal carbonates, such as sodium carbonate, potassiumcarbonate or caesium carbonate, alkaline earth metal carbonates, such ascalcium carbonate, or alkali metal or alkaline earth metal alkoxides,such as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, or organic amines(trialkyl(C₁-C₆)amines), such as triethylamine, or heterocycles, such as1,4-diazabicyclo[2.2.2]octane (DAPCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, diaminopyridine,methylpiperidine or morpholine. It is also possible to use, as bases,alkali metals, such as sodium, or their hydrides, such as sodiumhydride. Preference is given to sodium hydride, potassium carbonate,caesium carbonate, triethylamine, trimethylamine, pyridine, potassiumtert-butoxide, DBU or DABCO. Very particularly preferred for the step[A] (II)+(III)→(IV) are sodium hydride and sodium hydroxide.

In general, the base is employed in an amount of from 0.05 mol to 10mol, preferably from 1 mol to 2 mol based on 1 mol of the compound ofthe formula (II).

The process (II)+(III)→(IV) according to the invention is generallycarried out in a temperature range from −20° C. to +100° C., inparticular from −20° C. to +60° C., preferably from 0° C. to +60° C.

The process (II)+(III)→(IV) according to the invention is generallycarried out under atmospheric pressure. However, it is also possible tocarry out the process under elevated pressure or under reduced pressure(for example in a range from 05 to 5 bar).

The hydrolysis of the carboxylic esters is carried out by customarymethods by treating the esters in inert solvents with customary bases,the salts which are formed initially being converted by treatment withacid into the free carboxylic acids, or, in the case of the t-butylesters, with acid.

Suitable bases for the hydrolysis are the customary inorganic bases.These preferably include alkali metal hydroxides or alkaline earth metalhydroxides, such as, for example, sodium hydroxide, lithium hydroxide,potassium hydroxide or barium hydroxide, or alkali metal carbonates,such as sodium carbonate or potassium carbonate or sodium bicarbonate.Particular preference is given to using sodium hydroxide or lithiumhydroxide.

Suitable acids are, in general, trifluoroacetic acid, sulphuric acid,hydrogen chloride, hydrogen bromide and acetic acid, or mixture thereof,if appropriate with addition of water. Preference is given to hydrogenchloride or trifluoroacetic acid in the case of the tert-butyl estersand to hydrochloric acid in the case of the methyl esters.

Solvents which are suitable for the hydrolysis are water or the organicsolvents customarily used for hydrolysis. These preferably includealcohols, such as methanol, ethanol, propanol, isopropanol or butanol,or ethers, such as tetrahydrofuran or dioxane, dimethylformamide,dichloromethane or dimethyl sulphoxide. It is also possible to usemixtures of the solvents mentioned. Preference is given towater/tetrahydrofuran and, in the case of the reaction withtrifluoroacetic acid, dichloromethane and, in the case of hydrogenchloride, tetrahydrofuran diethyl ether, dioxane or water.

The hydrolysis is generally carried out in a temperature range from 0°C. to +100° C.

In general, the hydrolysis is carried out at atmospheric pressure.However, it is also possible to operate under reduced pressure or underelevated pressure (for example from 0.5 to 5 bar).

When carrying out the hydrolyses, the base or the acid is generallyemployed in an amount of from 1 to 100 mol, preferably from 1.5 to 40mol, based on 1 mol of the ester.

Preferred auxiliaries used for the amide formations are condensingagents. Preference is given here to using the customary condensingagents, such as carbodiimides, for example N,N′-diethyl-,N,N′-dipropyl-, N,N′diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) orcarbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazoliumcompounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds,such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic acid anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride orbenzotriazolyloxy-tri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl) N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU) or O-(7-azabenzotriazol-1-yl) N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU) and, as bases, alkali metal carbonates, forexample sodium carbonate or bicarbonate or potassium carbonate orbicarbonate, or organic bases, such as trialkylamines, for exampletriethylamine, N-ethylmorpholine, N-methylpiperidine ordiisopropylethylamine. Particular preference is given to the combinationof EDC, N-methylmorpholine and 1-hydroxybenzotriazole.

The compounds of the general formulae (II), (IIIa), (VI) and (VIII) areknown or can be prepared by customary methods (cf. EP-A-0 725 061,EP-A-0 725 064).

Most of the compounds of the general formula (III) are novel, and theycan be prepared, in the case that R¹¹ does not represent a heterocyclewhich is attached directly via N, by reacting compounds of the generalformula (XI)

-   in which-   A, D, E, G and L₁ are each as defined above-   with compounds of the general formula (XII)    R¹¹—CO₂H  (XII)-   in which-   R¹¹ is as defined above-   or, if appropriate, esters, lactones or other reactive precursors    thereof (for example imido esters)-   if appropriate with removal of the water of reaction, if appropriate    in the presence of an acid, preferably PPA, HCl and p-TsOH (cf.    also J. Org. Chem. 1941, 6, 25 ff. and Bull. Soc. Chim. Fr. 1991,    128, 255-259)-   and, in the case that R¹¹ represents one of the radicals listed    above under R² which optionally also carries a protective group, by    converting compounds of the general formula (XI) initially by    reaction with compounds of the general formula (XIII)    HO—R¹⁴—CO₂H  (XIII)-   in which-   R¹⁴ represents (C₁-C₈)-alkanediyl-   or, if appropriate, esters, lactones or other reactive precursors    thereof (for example imido esters)-   into the compounds of the general formula (XIV)-   in which-   A, B, D, G, R¹⁴ and L¹ are each as defined above-   in inert solvents,-   subsequently substituting the hydroxyl group by halogen, mesylate or    tosylate, thus producing the compounds of the general formula (XV)-   in which-   R¹⁴, A, D, E, G and L¹ are each as defined above-   and-   Z represents halogen, mesylate or tosylate,-   and reacting these with amines of the general formula (XVI)    R⁸R⁹NH  (XVI)-   in which-   R⁸ and R⁹ are each as defined above-   (cf. also J. Am. Chem. Soc. 1948, 70, 3406; J. Heterocycl. Chem.    1969, 759-60).

Solvents which are suitable for the process are customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, pyridine, dimethyl sulphoxide,dimethylformamide, N,N′-dimethylpropyleneurea (DMPU),N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane. It isalso possible to use mixtures of the solvents mentioned. Preference isgiven to dichloromethane, tetrahydrofuran and dimethylformamide.

Bases suitable for use in the process according to the invention are, ingeneral, inorganic or organic bases. These preferably include alkalimetal hydroxides, such as, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides, such as, for example, bariumhydroxide, alkali metal carbonates, such as sodium carbonate, potassiumcarbonate or caesium carbonate, alkaline earth metal carbonates, such ascalcium carbonate, or alkali metal or alkaline earth metal alkoxides,such as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, or organic amines(trialkyl(C₁-C₆)amines) such as triethylamine, or heterocycles such as1,4-diazabicyclo-[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,methylpiperidine or morpholine. It is also possible to use, as bases,alkali metals, such as sodium, or their hydrides, such as sodiumhydride. Preference is given to sodium hydride, potassium carbonate,triethylamine, trimethylamine, pyridine, potassium tert-butoxide, DBU orDABCO.

In general, the base is employed in an amount of from 0.05 mol to 10mol, preferably from 1 mol to 2 mol, based on 1 mol of the compound ofthe formula (XV).

The process according to the invention is generally carried out in atemperature range of from −50° C. to +100° C., preferably from −30° C.to +60° C.

The process according to the invention is generally carried out underatmospheric pressure. However, it is also possible to carry out theprocess under elevated pressure or under reduced pressure (for examplein a range from 0.5 to 5 bar).

The compounds of the general formulae (XII), (XII) and (XVI) are knownper se or can be prepared by customary methods.

Some of the compounds of the general formulae (XV) and (XV) are novel,and they can be prepared by customary methods, for example as describedabove.

The compounds of the general formulae (IV), (V), (VII), (DC) and (X) andtheir salts are novel and can be prepared as described above.

Surprisingly, the compounds of the general formula (I) according to theinvention and their analogues have an unforeseeable usefulpharmacological activity spectrum, combined with an improved solubilityin water, which may, if appropriate, only be achieved with the aid offormulation auxiliaries and/or by establishing a suitable pH, and, ifappropriate, also combined with increased metabolic stability.

Accordingly, they can be employed for preparing medicaments for thetreatment of all disorders caused by ischaemia, in particular for theacute and chronic treatment of ischaemic disorders of the cardiovascularsystem (such as, for example, coronary heart disease, stable andunstable angina pectoris, of peripheral and arterial occlusive diseases,of thrombotic vascular occlusions, of myocardial infarction and ofreperfusion damage).

Moreover, owing to their potential to increase angiogenesis, they areparticularly suitable for a permanent therapy of all occlusive diseases.The substances are therefore suitable for treating all peripheral andcardiovascular disorders caused by ischaemia, i.e. disorders of thecardiovascular system caused by ischaemia. For pharmaceutically activecompounds and active compound formulations, a good solubility in wateris, as is well known, an advantageous property, thus, the compoundsaccording to the invention are, for example, particularly suitable fororal and intravenous administration.

Test systems

1. Determination of the Solubility

To determine the solubility, a precipitation method was used:

10 mg of the test substance are completely dissolved in 50 μl of DMSO(stock solution). 20 μl of this solution are added to 2000 μl ofphysiological saline. This solution, in turn, is shaken at 25° C. in aThermomixer Comfort (from Eppendorf) at 1400 rpm for 24 hours forequilibration

The precipitated fractions of the test substance are centrifuged offusing a Biofuge 15 from Heraeus at 14,000 rpm for 5 min. 1300 μl of thesupernatant are once more centrifuged using a Microfuge from Beckmann at45,000 rpm=125,000 go

10 μl of this centrifugation supernatant are then diluted with 1000 pdof DMSO, and this solution is measured by HPLC (Hewlett Packard 1090,method, gradient from 100% PBS buffer pH=4 to 10% buffer/90%acetonitrile over a period of 15 min, column: RP18).

Using a calibration curve, the measured peak area of the HPLCmeasurement is converted into the substance concentration. For thecalibration curve, 20 μl of the stock solution are diluted successivelywith DMSO such that 5 concentrations of 2.5 mg/l to 2000 mg/l result.These solutions are likewise measured by HPLC (see method above), andthe peak areas are plotted as a function of the concentrations.

2. Inhibition of Adenosine Uptake in Rabbit Erythrocytes by theCompounds According to the Invention.

The capability of substances to influence the adenosine-uptake system isinvestigated by determining the inhibitory effect of the substances onfunctional adenosine uptake. For the functional adenosine-uptake test,an erythrocyte preparation from rabbit blood is used. The blood is drawnintravenously using citrate (3 ml Monovette 9NC from Sarstedt) asanticoagulant. The blood is centrifuged at 3000 g for 5 min and theerythrocytes are suspended in 10 mM MOPS/0.9% NaCl solution pH 7.4. Thesuspension is diluted to one hundredth of the original blood volume. Ineach case 990 μl of the suspension are admixed with 10 μl of a suitableconcentration of the substance to be investigated, and the mixture isincubated at 30° C. for 5 min. 5 μl of a 4 mM adenosine solution arethen added, and the mixture is incubated at 30° C. for another 15 min.The samples are then centrifuged at 3000 g for 5 min and in each case700 pd of the supernatant are admixed with 28 μl of 70% strength HClO₄,allowed to stand in an ice bath for 30 min and centrifuged at 16,000 gfor 3 min, and 350 μl of the sample are neutralized using 30 μl of 5NNaOH. 50 μl of the sample are applied to a column (Waters Symmetry C1851 μm 3.9×150 mm). A Spherisorb ODS II 5 μm 4.6×10 mm column is used asprecolumn. The mobile phase used is a gradient of 50 mM KH₂PO⁴/5 mMtributylamine pH 7 (mobile phase A) and a mixture of mobile phaseA/methanol 1/1 (mobile phase B). The gradient is from 10-40% B, at aflow rate of 0.5 ml/min. The adenosine which is present is quantified byits absorption at 260 nm, as are the hyoxanthine and inosine formed. TheIC₅₀ is the concentration of active compound at which, 15 min afteraddition of adenosine, 50% of the adenosine concentration originallyemployed is still present.

Using this test, the IC₅₀ value determined for Example 3 was 15 nM, thatfor Example 8 was 20 nM, that for Example 10 was 25 nM and that forExample 16 was 10 nM.

3. In vivo Test Model for Testing “Adenosine-Reuptake Inhibitors”

Adult FBI (Foxhound-Beagle-Irish-Setter) dogs (20-30 kg) are initiallyanaesthetized using a combination of trapanal 500 mg and alloferin 55mg. Anaesthesia is maintained by infusion of a mixture of fentanyl 0.072mg/kg, alloferin 0.02 mg/kg and dihydrobenzpyridyl 0.25 mg/kg×min. Theanimals are intubated and ventilated with a mixture of O₂/N₂O 1/5 usingan Engström ventilation pump at 16 breaths per min and a volume of 18-24ml/kg. The body temperature is maintained at 38° C.±0.1° C. Arterialblood pressure is measured via a catheter in the femoral artery.Thoracotomy is carried out on the left side at the fifth intercostalspace. The lung is pushed back and fixed and a cut is made in thepericardium. A proximal section of the LAD distally to the firstdiagonal branch is exposed and a calibrated electromagnetic flow sensor(Gould Statham, model SP7515) is placed around the vessel and attachedto a flow meter (Statham, model SP-2202). Distally to the flow sensor, amechanic occluder is attached such that there are no branches in betweenflow sensor and occluder.

Using a catheter in the femoral vein, blood samples are taken andsubstances administered. A peripheral ECG is recorded using needleswhich are fixed subcutaneously. A microtip pressure manometer (Millarmodel PC-350) is pushed through the left atrium to measure the pressurein the left ventricle. Measurement of the heart frequency is triggeredby the R wave of the ECG. During the entire experiment, the haemodynamicparameters and coronary flow are recorded using a multi-event recorder.

A four-minute occlusion causes reactive hyperaemia. The differencebetween the coronary flow under control conditions and the maximum flowduring the reactive hyperaemia is measured. The time which is requiredto achieve half of this maximum flow in the drop is a suitable parameterto assess the reactive hyperaemia.

After a stabilization period of one hour, the experiment is started witha four-minute occlusion. Thirty minutes later, the substance isadministered (i.v.) which is, after two minutes, followed byre-occlusion. The reactive hyperaemia after verum and placebo iscompared.

4. Mouse Angiogenesis Model

To test the effect of adenosine-reuptake inhibitors on collateralizationand neovascularization a mouse model for angiogenesis was developed. Tothis end, a femoral artery of the mouse is ligated at the upper end ofthe thigh. This induces chronic ischaemia of the hind leg in question.The other hind leg serves as individual control. To exclude residualflow through the ligated vessel, two ligatures are applied, and thevessel is cut in between. A few days after this operation, the treatmentis started.

As a measurement parameter during the ongoing experiment, thetemperatures of the paws of the two hind legs are measured. Owing topoorer circulation, the ischaemic hind leg has a lower absolutetemperature. In each case, the temperature difference between the pawsof the hind legs is calculated. This individual temperature differenceis determined in different treatment groups as a function of the doseand in comparison with an untreated control. In this model,adenosine-reuptake inhibitors significantly improve the circulation ofthe ischaemic hind leg in comparison with the corresponding controls.

The novel active compounds can be converted in a known manner into thecustomary formulations, such as tablets, sugarcoated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable carriers or solvents. Inthis connection, the therapeutically active compound should in each casebe present in a concentration of approximately 0.5 to 90% by weight ofthe total mixture, i.e. in amounts which are sufficient in order toachieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or carriers, if appropriate usingemulsifiers and/or dispersants, where, for example, if the diluent usedis water, organic solvents can optionally be used as auxiliary solvents.

Administration is carried out in a conventional man ner, preferablyorally, transdermally, parenterally, perlingually, intravenously,particularly preferably orally or intravenously.

In general, it has proven advantageous in the case of intravenousadministration to administer amounts of approximately 0.0001 to 10mg/kg, preferably approximately 0.003 to 1 mg/kg, of body weight, toachieve effective results. In the case of oral administration, 0.1 to 20mg/kg, preferably 0.3-3 mg/kg, of body weight are employed.

In spite of this, if appropriate it may be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on the individual response towards the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the above-mentioned minimum amount, while in othercases the upper limit mentioned has to be exceeded. It may be advisableto divide this amount into a number of individual doses over the courseof the day.

Starting materials

The following abbreviations for solvents are used in the examples:

-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulphoxide-   PPA=polyphosphoric acid-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran

EXAMPLE 1A

(1R, 2R)-2-(4-Methyl-phenyl)-cyclohexane-1-carboxylic acid

Racemic (1R*,2R*2)-(4-methyl-phenyl)-cyclohexane-1-carboxylic acid wasprepared analogously to the process described in U.S. Pat. No.5,395,840, column 16. The resulting racemic material was separated intothe enantiomers using the following procedure:

The racemic acid (415 g; 1.9 mol) and triethylamine (96.2 g; 0.95 mol;131.8 ml) were suspended in a mixture of THF (2.7 1) and water (5.3 1).At 60° C., (S)-(−)phenylethylamine (115.2 g; 0.95 mol) was addeddropwise, resulting in a precipitate being formed. The mixture wasstirred at 60° C. for 2 h and then cooled using an ice bath. Thisprecipitate was filtered off with suction, giving predominantly thephenylethylamine salt of the (1S,2S)-enantiomer. The filtrate wasacidified using conc. HCl and extracted twice using dichloromethane. Thecombined extracts were dried over sodium sulphate and concentrated.Yield: 202.4 g (28%) of a mixture of enantiomers enriched with the(1R,2R)-isomer.

This mixture was treated with R-(+)-phenylethylamine as described aboveto precipitate the desired enantiomer as a salt. The colourless crystalswere filtered off with suction and recrystallized fromacetonitrile/methanol (6:1). X-ray analysis of these crystals confirmedthe (1R, 2R)-configuration. Yield 136.9 g (46%). Work-up (see above)gave 89 g of (1R, 2R)-2-(4-methylphenyl)-cyclohexane-1-carboxylic acid.

EXAMPLE 2A

tert-Butyl (1R, 2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylate:

The intermediate was prepared analogously to the procedure for theracemate (U.S. Pat. No. 5,395,840, column 17). For purification, theresulting mixture was stirred with diethyl ether.

EXAMPLE 3A

2-(2-Phthalimidylethyl)-1H-benzimidazole

2-Aminoethylbenzimidazole dihydrochloride (Bull. Soc. Chim. Fr. 1991,128, 255-259; 2.34 g, 10 mmol), phthalic anhydride (1.63 g, 11 mmol) andtriethylamine (2.79 ml, 20 mmol) in chloroform (25 ml) were heated atreflux overnight, and the mixture was then cooled to room temperature,diluted with ethyl acetate and filtered off. The filtrate was washedwith saturated sodium carbonate solution, buffer (pH=7) and saturatedsodium chloride solution and dried over sodium sulphate. Chromatography(dichloromethane:methanol 10:1, R_(f)=0.4) gave 2.08 g of2-(2-phthalimidylethyl)-benzimidazole (71.4% of theory) as a colourlessfoam. MS (DCI, NH₃)=292 (M+H⁺). ¹H-NMR (DMSO-d₆): 3.15 (2H, t); 4.0 (2H,t); 7.05-7.2 (2H, m); 7.4-7.5 (2H, m); 7.8-7.9 (4H, m); 12.4 (1H, br s).

The remainder of the synthesis is carried out following the generalprocedures A, B and C as mentioned below, and in a last step, thephthalimide group is cleaved off as described below.

EXAMPLE 4A

2-(2-Hydroxyethoxymethyl)-pyrido[2,3-d]-1H-imidazole

1,4-Dioxan-2-one (6.13 g, 60 mmol) and 2,3-diaminopyridine (5.46 g, 50mmol) in mesitylene (100 ml) were heated at reflux in a Dean-Starkseparator for 10 h. After cooling, mesitylene was decanted off and theresidue was purified by silica gel chromatography(dichloromethane:methanol 9:1) (yield: 8.47 g, 87% of theory).

MS(DCI)=194 (M+H, 100%); ¹H-NMR (DMSO-d₆): 3.78 (2H, m); 3.89 (2H, m);4.91 (2H, s); 5.3 (1H, s); 7.18 (1H, dd); 7.95 (1H, d); 8.43 (1H, dd);12.7 (1H, br s).

EXAMPLE 5A

2-[2-(tert-Butyldimethylsilyloxy)ethoxymethyl]-pyrido[2,3-d]-1H-imidazole

8.4 g (43.48 mmol) of2-(2-hydroxyethoxymethyl)(pyrido-[2,3-d]-1H-imidazole) and 4.84 g (47.82mmol) of triethylamine were dissolved in 120 ml of DMF and admixed with7.21 g (47.8 mmol) of TBDMS chloride, the mixture warming to about 40°C. Stirring at room temperature was continued for 2 h, and the mixturewas then poured into water, giving the product in crystalline form. Theproduct was filtered off with suction, washed with a little water anddried under high vacuum. ¹H-NMR (DMSO-d₆): 0.02 (6H, s); 0.83 (9H, s);3.52 (2H, t); 3.75 (2H, t); 4.73 (2H, s); (1H, dd); 7.90 (1H, dd); 8.43(1H, dd); 12.9 (1H br s).

EXAMPLE 6A

2-tert-Butyldimethylsilyloxymethyl-1H-benzimidazole:

At room temperature, triethylamine (2.27 ml, 16.3 mmol) and TBDMSchloride (1.65 g, 10.95 mmol) were added to a solution of2-hydroxymethylbenzimidazole (1.48 g, 9.95 mmol) in DMF-(30 ml). After3.5 h, the reaction-was terminated by addition of water, the mixture wasextracted with diethyl ether and the organic phase was dried over sodiumsulphate. Chromatography (silica gel, cyclohexane:ethyl acetate 2:1,R_(f)=0.35) gave 2.52 g of2-tert-butyldimethylsilyloxymethyl-benzimidazole (97% of theory) as abrownish powder. MS (DCI, NH₃)=263 (M+H⁺). ¹H-NMR (DMSO-d₆): 0.00 (6H,s); 0.80 (9H, s); 4.75 (2H, s); 7.0-7.1 (2H, m); 7.4-7.5 (2H, m); 12.15(1H, br s).

EXAMPLE 7A

2-(2-Hydroxyethoxymethyl)-1H-benzimidazole:

Using a Dean-Stark separator, 1,4-dioxan-2-one (2.04 g, 20 mmol) and1/2-diaminobenzene (2.16 g, 20 mmol) were heated under reflux inmesitylene (150 ml) for 10 h. The crystals formed on cooling were thenfiltered off with suction (2.94 g, 77% of theory). R_(f)(dichloromethane:methanol 10:1)=0.45, MS (EI)=192 (M+, 20%), 148 (20%),147 (40%), 132 (100%4), ¹H-NMR (DMSO-d₆): 3.6 (4H, s); 4.65 (1H, s); 4.7(2H, s); 7.1-7.2 (2H, m); 7.45 (1H, d); 7.55 (1H, d); 12.4 (1H, br s).

EXAMPLE 8A

2-(3{[tert-Butyl(dimethyl)silyl]oxy}propyl)-1H-benzimidazole

The silylation of 2-(3-hydroxypropyl)-1H-benzimidazole was carried outanalogously to the process described in Example 6A.

To this end, tert-butyldimethylsilyl chloride (TBDMSCI) (14.68 g, 97.37mmol) was added a little at a time to a solution of2-(3-hydroxypropyl)-benzimidazole (15.60 g, 88.52 mmol) in DMF (265 ml)and triethylamine (20.27 ml, 145.41 mmol). The mixture was stirred at RTovernight and then admixed with water (800 ml) and extracted withdiethyl ether. The organic phase was dried over sodium sulphate andchromatographed over silica gel (mobile phase: cyclohexane/ethylacetate=6:1), giving 25 g (97%) of colourless crystals. MS (DCI): 291(M+H)+

¹H-NMR (CDCl₃): 0.12 (6H, s); 0.92 (9H, s); 2.08 (2H, m); 3.10 (2H, t);3.80 (2H, t); 7.20 (2H, m); 7.52 (2H, br. s).

EXAMPLE 9A

(S)-(4-Fluorophenyl)glycinamide hydrochloride

Route 1:

a) (S)-N-(tert-Butoxycarbonyl)-(4-fluorophenyl)glycine

(S)-(4-Fluorophenyl)glycine (35 g, 207 mmol) and sodium carbonate (54.8g, 517 mmol) were initially charged in water (150 ml) andtetrahydrofuran (75 ml), and di-tert-butyl pyrocarbonate (Boc anhydride)(52.3 ml, 228 mmol) was added dropwise at room temperature. The reactionmixture was stirred overnight at RT. Using 5N hydrochloric acid, thereaction solution was adjusted to pH 3 and extracted withdichloromethane and water, and the aqueous phase was re-extracted twicewith dichloromethane. The combined organic phases were dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The product (54.2 g, 97% of theory) was reacted without anyfurther purification.

MS (ESI)=561 (2M+Na⁺, 40%), 292 (M+Na⁺, 100%), 236 (40%), 214 (70%), 153(95%).

¹H-NMR (DMSO-d₆): 1.38 (9H, s); 5.11 (1H br. d); 7.12-7.21 (2H, m);7.39-7.47 (2H, m); 7.56 (1H, br. d); 12.78 (1H, br. s).b) (S)-N-(tert-Butoxycarbonyl)-(4-fluorophenyl)glycinamide

Under argon, the product from Example 9A a) (54.2 g, 201 mmol) wasdissolved in tetrahydrofuran (600 ml), the mixture was cooled to −15° C.(internal temperature) and triethylamine (201 mmol, 28.1 ml) andisobutyl chloroformate (201 mmol, 26.1 ml) were added successively overa period of 5 min. The mixture was stirred at −15° C. for 25 min, afterwhich ammonia in methanol (126 ml of a 2N solution) was added, and thereaction mixture was stirred at this temperature for 30 min. The mixturewas filtered and the filter residue was dissolved in dichloromethane andextracted with water. The organic phase was washed twice with sodiumcarbonate solution and dried over sodium sulphate, and the solvent wasremoved under reduced pressure. The residue was admixed with petroleumether and crystallized at 4° C. overnight. After filtration and rinsingwith petroleum ether, the product (33.9 g, 63% of theory) was isolatedas a solid.

-   R_(f)(methanol:dichloromethane=1:10)=0.46

MS (DCI/NH₃)=269 (M+H⁺, 60%), 169 (100%).

¹H-NMR (DMSO-d₆): 137 (9H, s); 5.09 (1H, br. d); 7.1-7.3 (4H, m);7.37-7.51 (2H, m); 7.57 (1H, br. s).c) (S)-(4-Fluorophenyl)glycinamide hydrochloride

The product from Example 9A b) (33.8 g, 126 mmol) was dissolved in asolution of hydrogen chloride in 1,4-dioxane (250 ml of a 4N solution)and 1,4-dioxane (100 ml), and the mixture was stirred at RT for 2 h. Theresulting precipitate was filtered off with suction, washed with diethylether and, after drying under reduced pressure, triturated once morewith diethyl ether, filtered off with suction and dried under reducedpressure. The product was isolated as a colourless solid (24.3 g, 94.4%of theory) of an enantiomeric purity>99% ee.

MS (DCI/NH₃)=337 [2(M−HCl)+H⁺, 20%], 169 [(M−HCl)+H⁺, 100%].

¹H-NMR (DMSO-d₆): 4.97 (1H, s); 7.2-7.4 (2H, m); 7.5-7.7 (2H, m); 8.13(1H, s); 8.80 (3H, s).

Route 2:

Alternatively to route 1, it was possible to prepare the compound fromExample 9A c), i.e. (S)-(4-fluorophenyl)glycinamide hydrochloride, bythe following route:

i) rac-(2-Benzylamino)-2-(fluorophenyl)acetonitrile [rac-(3)]

4-Fluorobenzaldehyde is initially reacted with benzylamine in a cyanidesolution in acetic acid in a so-called Strecker reaction, which is oneof the standard reactions in amino acid syntheses (see, for example, thefour literature references: 1.) Hassan, N. A., Bayer, E., Jochims, J.C., J.Chem.Soc. Perkin 1 1998, 3747-3757; 2.) Georgiadis, M. P.,Haroutounian, S. A., Synth. Comm. 1989, 616; 3.) Alabaster, RJ., Gibson,A. W., Johnson, S. A., Edwards, J. S., Cottrell, I. F., TetrahedronAsymmetry 1997, 8, 447-450, quoted therein: Alabaster, R. J.; Cottrell,I. F.; Gibson, A. W.; Johnson, S. A.: UK Patent Appl. 9511031.8; 4.)Inaba, T., Fujita, M., Oguia, K, J.Org.Chem. 1991, 56, 1274-1279).

Under the conditions described in literature reference 1.) (Hassan, N.A., Bayer, E., Jochims, J. C., J.Chem.Soc. Perkin 1 1998, 3747-3757),the racemic (2-benzylamino)₂₄-fluorophenyl)acetonitrile [rac-(3)] wasprepared in a yield of 85%.ii) (S)-Benzyl[cyano(4-fluorophenyl)methyl]ammonium(R)-amygdalate[(S,R)-(4)]

The racemic product from Example 9A i) was then dissolved in ethanol andadmixed with (R)-mandelic acid to isolate, in a kinetic racemateseparation, the diastereomerically pure(S)-benzyl[cyano(4-fluorophenyl)methyl]ammonium (R)-amygdalate (seeliterature reference 1.) above, J.Chem.Soc. Perkin 11998, 3747-3757).63% of the diastereomerically pure product was isolated here.iii) (2S)N-Benzyl-(4-fluorophenyl)acetonitrile [(S)-(3)]

From the product from Example 9A ii), the enantiomerically pure(2S)-N-benzyl-(4-fluorophenyl)acetonitrile was obtained in a yield of87% (see literature reference 1.), J.Chem.Soc.Perkin 1 1998, 3747-3757).iv) (2S)-N-Benzyl-(4-fluorophenyl)glycinamide

The enantiomerically pure (2S)-N-benzyl-(4-fluorophenyl)acetonitrilefrom Example 9A iii) was hydrolysed using conc. sulphuric acid to give(2S)-N-benzyl-(4-fluorophenyl)glycinamide in a yield of 97% (seeliterature reference 1.), J.Chem.Soc. Perkin 1 1998, 3747-3757).

For the conversion of rac-3) into racemicN-benzy-(4-fluorophenyl)glycinamide, an alternative method usingH₂O₂/K₂CO₃ is described in the prior art (see literature reference 3.),Alabaster, R. J., Gibson, A. W., Johnson, S. A., Edwards, J. S.,Cottrell, I. F., Tetrahedron Asymmetry 1997, 8, 447450, cited therein:Alabaster, R. J.; Cottrell, I. F.; Gibson, A. W.; Johnson, S. A.: UKPatent Appl. 9511031.8).(S)-(4-Fluorophenyl)glycinamide hydrochloride

For the debenzylation, which has hitherto not been described, of theproduct from Example 9A iv), a solution of this product (1.5 g, i.e. 5.8mmol of (2S)N-benzy-(4-fluorophenyl)glycinamide) in ethanol (37.5 ml)was admixed with 50% water-moist 5% palladium-on-carbon (1.5 g),ammonium formate (1.5 g, 23.8 mmol) and water (18.8 ml), and thismixture was heated to reflux temperature. After 2 h at reflux, themixture was filtered, the palladium-on-carbon was washed with coldethanol (two times 3 ml) and the solution was concentrated. The crudeproduct was stirred with a little ethyl acetate, once more filtered offwith suction and concentrated to dryness. The evaporation residue wasadmixed with 1N HCl in ether and evaporated to dryness. The colourlessproduct was dried under reduced pressure. 0.6 g of the product(S)-4-fluorophenylglycinamide hydrochloride (50% of theory) wasisolated. The MS and ¹H-NMR-spectroscopic data corresponded to thosegiven above in Example 9A c).

General Procedure for Alkylation [A]:

In a typical batch, sodium hydride (6.3 mmol) was, at 0° C., added to asolution of the imidazole of the general formula (III) (6 mmol) in dryDMF (30 ml). After 30 min at room temperature and 30 min at 40° C., thecompound of the general formula (II) (6.3 mmol) was added at 0° C., andthe reaction mixture was stirred at room temperature overnight. Thereaction was then terminated by addition of water, the mixture wasextracted with diethyl ether and the organic phase was then dried oversodium sulphate. Chromatography (silica gel, cyclohexane:ethyl acetate)gave the product in a yield of 60-90%.

Alternatively to the reaction of the imidazole with sodium hydride inDMF, it is also possible to carry out the reaction using sodiumhydroxide in THF.

General Procedure for Ester Hydrolysis [B]:

In a typical batch, trifluoroacetic acid (5 ml) was added at roomtemperature to a solution of the ester of the general formula (IV)(T=tert-Bu; 1.5 mmol) in dichloromethane (5 ml). After 2 h, the mixturewas cooled to 0° C., adjusted to pH=2 using aqueous sodium hydroxidesolution (about 30 ml, 2 M) and extracted with dichloromethane. Dryingof the organic phase over sodium sulphate gave, after concentration, thecompound of the general formula (V).

General Procedure for Amide Formation [C]:

A suspension of acid (V) (4 mmol), (S)-phenylglycinamide hydrochloride(4.2 mmol), 1-hydroxybenzotriazole (4.4 mmol), EDC hydrochloride (4.8mmol) and triethylamine (12 mmol) in dichloromethane ordimethylformamide (DMF) (40 ml) was stirred at room temperature for24-48 h. Water was added, and the mixture was then extracted withdichloromethane (in some cases with methanol) and the organic phase wasdried over sodium sulphate (or magnesium sulphate) and chromatographed(silica gel, dichloromethane: methanol). This gave the desired productin a yield of 60-80%.

Analogously to procedure C, it is possible to employ phenylglycinolinstead of phenylglycinamide.

PREPARATION EXAMPLES EXAMPLE 1

(S)-N-{(1R*,2R*)-{4-[2-(2-Aminoethyl-benzimidazol-1-yl)methyl]phenyl}-cyclo-hex-2-yl-carbonyl}-phenylglycinamide

Hydrazine hydrate (0.38 ml, 7.82 mmol) was added to a suspension of(2S)-N-[(2R*)-(4-{2-(2-phthaloylaminoethyl)-benzimidazol-1-yl-methyl}-phenyl)-cyclohexyl-(1R*)-carbonyl]-phenylglycinamide (prepared according to the generalprocedures [A-C] from the compound of Example 3A and the racemate ofExample 2A according to U.S. Pat. No. 5,395,840, Example IV; 500 mg,0.78 mmol, mixture of diastereomers) in ethanol (25 ml). The mixture wasstirred at room temperature overnight and then adjusted to pH=2 usinghydrochloric acid (1 M) and concentrated. The mixture was partitionedbetween 10% aqueous sodium bicarbonate solution and dichloromethane andthe organic phase was dried over sodium sulphate and chromatographed(silica gel, dichloromethane:methanol:conc. aqueous ammonium 100:13:1.3,R_(f)(10:1:0.2)=0.1), giving the title compound (292 mg, 72%, mixture ofdiastereomers) as a yellowish powder. MS(DCI, NH₃)=510 (M+H⁺).¹H-NMR(DMSO-d₆): 1.2-1.5 (4H, m); 1.6-1.9 (4H, m); 2.0 (2H, br s);2.6-3.0 (6H, m); 5.1-5.2 (A:1 H, d; B:1 H, d); 5.4-5.5 (A:2H, s; B:2H,s); 6.85-7.0 (4H, m); 7.1-7.3 (7H, m); 7.4-7.5 (1H, m); 7.55-7.65 (4H,m); 8.05-8.15 (A:1 H, d; B:1 H, d).

EXAMPLE 2

(S)-N-{(1R,2)-{4-{[2-(2-Aminoethyl)-benzimidazol-1-yl]methyl}phenyl}cyclohex-1-yl-carbonyl}phenylglycinamidedihydrochloride

Chromatographic separation of the starting material from Example 1(silica gel, methylene chloride:methanol) gave diastereomerically pure(S)-(N)-{(1R,2R)-2-{4-{2-[2(phthaloyl-amino)ethyl]-benzimidazol-1-yl-methyl}-phenyl}-cyclohex-1-yl-carbonyl}-phenylglycinamidewhich was deprotected analogously to Example 1 and then dissolvedcompletely in as small an amount of dichloromethane as possible, treatedwith about two equivalents of 1M HCl in diethyl ether and concentrated.

Found: C64.21H6.58

Calc.: C63.91H 6.49

EXAMPLE 3

(S)-N-{{(1R,2R)-{4-{2-[2-(Morpholin-4-yl-methyl)-1H-pyrido[2,3-d]-imidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl}carbonyl}-phenylglycinamide

2-Hydroxymethyl-1H-pyrido[2,3-d]imidazole

2,3-Diaminopyridine (54.6 g; 0.5 mol) and glycolic acid (38 g; 0.5 mol)in 700 ml of mesitylene were heated under reflux using a Dean-Starkseparator until the calculated amount of water had separated out. Themixture was then cooled to room temperature and the resultingprecipitate was filtered off with suction and boiled in 800 ml of water,with addition of activated carbon, for 15 min. The hot suspension wasfiltered and cooled to room temperature, and colourless crystals thenprecipitated out, which were filtered off with suction and dried. Yield:56.4 g (75%).b) 2-Choromethyl-1H-pyrido[2,3-d]imidazole hydrochloride:

The compound from Example 3a (14.9 g; 100 mmol) was suspended in 25 mlof ethanol and a stream of dry HCl was introduced until saturation hadbeen reached. The resulting hydrochloride was filtered off with suctionand dried under reduced pressure. Yield 18.1 g (100%). The product wassuspended in 100 ml of chloroform and admixed with 35 ml of thionylchloride. The mixture was then heated under reflux for 24 h and thenfiltered hot, and the precipitate was washed with chloroform and driedunder reduced pressure. Yield 18.9 g (92%).c) 2-(Morpholin-4-yl-methyl)-1H-pyrido[2,3-d]imidazole:

The compound from Example 3b (13.7 g; 67 mmol) and morpholine (28.6 g,328 mmol) were heated under reflux for 3 h. The mixture was concentratedand the residue was taken up in sodium bicarbonate solution. Thissuspension was admixed with activated carbon and boiled for 15 min andthen filtered whilst still hot. The mixture was concentrated and theresulting product was then purified by column chromatography (silica gel(70-230 mesh ASTM); mobile phase: 100:30:1 ethylacetate/ethanol/triethylamine). The product can be recrystallized fromethyl acetate/hexane.d) tert-Butyl(1R,2R)-{4-{[2-(morpholin-4-yl-methyl)-1H-pyrido[2,3-d]-imidazol1-yl]methyl}phenyl}-cyclohexane-1carboxylate

Under argon, a 60% strength suspension of sodium hydride in oil (2 g;51.6 mmol) was suspended in 150 ml of DMF, and the compound from Example3 c) (9.5 g, 43.5 mmol) was added. The mixture was heated at 50° C. for30 min, resulting in the formation of a precipitate. The mixture wasthen cooled to room temperature and the compound from Example 2A (17.3g; 44 mmol) was added, and the mixture was then stirred at roomtemperature for 20 h. The resulting clear solution was concentratedunder high vacuum and the residue was taken up in dichloromethane/water.The organic phase was separated off, dried over sodium sulphate andconcentrated. The residue was then purified by column chromatography(silica gel (70-230 mesh ASTM); mobile phase: 100:4dichloromethane/methanol). Yield 10 g (47%) of a brown viscous oil.e)(1R,2R)-2-{4-{[2-Morpholin-4-yl-methyl)-1H-pyrido[2,3-d]imidazol-1-yl]-methyl}phenyl}cyclohexane-1-carboxylicacid

The compound from Example 3d (10 g; 20.4 mmol), 120 ml ofdichloromethane and 100 ml of trifluoroacetic acid were stirred at roomtemperature for 1 h. With cooling, the mixture was then neutralizedusing concentrated aqueous sodium hydroxide solution, and the organicphase was separated off, dried and concentrated. The residue waspurified by column chromatography (mobile phase:dichloromethane/methanol 100:6). Yield 7.3 g (80%) of a colourlessamorphous solid.f)(S)-N-{{(1R,2R)-2-{4-{[2-(Morpholin-4-yl-methyl)-1H-pyrido[2,3-d]imidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl}carbonyl}-phenylglycinamide

According to the general procedure [C], the compound from Example 3e(1.4 g; 3.22 mmol) was reacted with addition of a spatula tip of DMAP(4-dimethylaminopyridine). For work-up, the product was extracted withdichloromethane and purified by column chromatography(dichloromethane/methanol 100:6). Yield 1.7 g (93%) of a pale yellowishpowder.

¹H-NMR (300 MHz; CDCl₃) δ[ppm]: 1.25-1.5 (3H; br m), 1.62 (1H; dq), 1.8(3H; m), 1.94 (1H; dd), 2.31 (1H; dt), 2.42 (4H, br m), 2.67 (1H; dt),3.61 (6H; m), 5.21 (1H; d), 5.49 (1H, br s), 5.63 (2H; d+d), 5.72 (1H;br s), 6.41 (1H; d), 6.82 (2H; d), 6.92 (2H; d), 6.98 (2H; d), 7.13 (2H;t), 7.18 (1H; t), 7.23 (1H; dd), 8.03 (1H; d), 8.42 (1H; d)

MS (DCI/NH₃)[m/e]: 567 (100, M+H)

EXAMPLE 4

(S)-N-{{(1R,2R)-{4-{2-[2-(Morpholin-4-yl-methyl)-1H-pyrido[2,3-d]imidazol-1-yl]methyl}-phenyl}cyclohex-1-yl}carbonyl}-phenylglycinamidehydrochloride

The compound from Example 3 was dissolved completely in as small anamount of dichloromethane as possible and treated with approximately 2equivalents of 1M HCl in diethyl ether. The resulting precipitate wasfiltered off with suction [m.p. 158° C. (decomp.)].

EXAMPLE 5

(S)-N-{{(1R,2R)-2-{4-{[2-(4-Methyl-piperazin-1-yl)-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl}carbonyl}-phenylglycinamide

a) tert-Butyl (1R,2R)-2-{4-[(2-chloro-benzimidazol-1-yl)methyl]-phenyl}-cyclohexane-1-carboxylate

The title compound was prepared according to the general procedure [A]from 2-chlorobenzimidazole and the compound from Example 2A[R_(f)-(cyclohexane:ethyl acetate=1:1)=0.85].b)(1R,2R)-2-{4-{[2-(4-Methyl-piperazin-1-yl)-benzimidazol-1-yl]methyl}-phenyl}-cyclohexane-1-carboxylicacid

A solution of the compound from Example 5a (34.0 g, 56.0 mmol) inN-methylpiperazine (77.7 ml, 700 mmol) was heated at 100° C. overnightand then concentrated and chromatographed (silica gel,dichloromethane:methanol=20:1 to 10:1, R_(f) (10:1)=0.32). This gave32.0 g of tert-butyl (1R,2R)-2-{4-{[2-(4-methyl-piperazin-1-yl)benzimidazol-1-yl]methyl}-phenyl}-cyclohexane-1carboxylate which were reacted at room temperature with hydrochloricacid (180 ml, 6 M) overnight. The reaction mixture was washed at pH=7with dichloromethane and the organic phase was dried over magnesiumsulphate and chromatographed (silica gel, dichloromethane:methanol 5:1,R_(f)=0.13), giving 19 g (78% of theory over 2 steps) of the titlecompound. MS(ESI)=433 (M+H⁺). ¹H-NMR(DMSO-d₆): 1.35-1.5 (4H, m);1.65-1.8 (3H, m); 1.9-2.0 (1H, m); 2.2 (3H, s); 2.42.5 (5H, m); 2.6-2.7(1H, m); 3.15 (4H, Ψ t); 3.4 (1H, very br s); 5.2 (2H, s); 7.0-7.2 (7H,m); 7.4 (1H, d).c)(S)-N-{{(1R,2R)-2-{4-{[2-(4-Methyl-piperazin-1-yl)-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl}-carbonyl}-phenylglycinamide

A suspension of the compound from Example 5b (19 g, 43.9 mmol),(S)-phenylglycinamide hydrochloride (8.61 g, 46.1 mmol),1-hydroxybenzotriazol (7.68 g, 48.3 mmol), EDC hydrochloride (9.68 g,50.5 mmol) and triethylamine (24.5 ml, 175.7 mmol) in dichloromethane(1000 ml) was stirred at room temperature over the weekend. Afteraddition of water, the mixture was extracted withdichloromethane/methanol and the extract was dried over magnesiumsulphate and concentrated. The slightly yellowish solid was stirred withdichloromethane/methanol (10:1, 220 ml) and the pure title compound wasfiltered off and dried under reduced pressure at 40° C. (14.5 g, 59%).R_(f) (dichloromethane:methanol 10:1)=0.30. MS(DCI, NH₃)=565 (M+H⁺).¹H-NMR(DMSO-d₆): 1.2-1.5 (4 H, m); 1.6-1.85 (4 H, m); 2.2 (3 H, s); 2.45(4H, Ψ t); 2.65 (1 H, br t); 2.8 (H, td); 3.15 (4 H, Ψ t); 5.15 (1 H,d); 5.2 (2 H s); 6.9 (2 H, d); 6.95-7.2 (11 H, m); 7.45 (1 H, d); 7.6 (1H, br s); 8.0 (1 H, d).

EXAMPLE 6

(S)-N-{{(1R,2R)-2-{4-{[2-{(4-Methyl-piperazin-1-yl)-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl}carbonyl}-phenylglycinamidehydrochloride

The compound from Example 5 (100 mg, 0.177 mmol) was dissolved indichloromethane/methanol (2.5:1; 5 ml) and admixed with 1M HCl/diethylether (0.177 mmol), and the mixture was stirred for 5 min and thenconcentrated cold under reduced pressure. The title compound wasobtained as a colourless powder (106 mg). M.p. 200° C. (decomp.).

The Examples 7 to 10 listed in Table 1 below were prepared analogouslyto Example 5 using the appropriately substituted piperazines.

TABLE 1 Ex. No. Structure R_(f)* 7

0.3 (10:1:0)   8

0.3 (10:1:0.1) 9

0.4 (10:1:0.1) 10 

0.3 (10:1:0.1) *CH₂Cl₂:methanol:conc. ammonia

The Examples 11 and 12 listed in Table 2 below are prepared startingwith the compound from Example 6A, according to the general proceduresA, B and C.

TABLE 2 Ex. No. Structure R_(f)* 11

0.4 (10:1)  12

0.35 (10:1) *CH₂Cl₂:methanol

EXAMPLE 13

(S)-N-55 -55 (1R,2R)-2-{4-{[2-(2-Hydroxyethoxy)methyl]-benzimidazol-1-yl}methyl}-phenyl}-cyclohex-1-yl)carbonyl}-phenylglycinamide

The title compound is obtained starting with the compound of Example 7A,which is silylated analogously to Example 6A using TBDMS chloride andthen reacted according to the general procedures A, B and C.

R_(f)(dichloromethane:methanol 20:1)=0.20.

MS(ESI)=541 (M+H⁺). ¹H-NMR(DMSO-d₆): 1.2-1.5 (4H, m); 1.6-1.9 (4H, m);2.6-2.7 (1H, m); 2.75-2.85 (1H, m); 3.5 (4H, s); 4.65 (1H, br s); 4.6(2H, s); 5.15 (1H, d); 5.55 (2H, s); 6.9 (2H, d); 6.95-7.2 (10H, m);7.45 (1H, m); 7.6 (1H, s); 7.65 (1 H, m); 8.05 (1H, d).

The Examples 14 to 16 listed in Table 3 below are prepared analogouslyto Example 13 from the appropriate starting materials.

TABLE 3 R_(f) Ex. No. Structure (CH₂Cl₂:MeOH:conc. ammonia) MS 14

0.44 (10:1:0) 15

0.46 (10:1:0) 16

EI: 541 (M+)

EXAMPLE 17

(S)-N-{[(1R,2R)-2-{4-{[2-(3-Hydroxypropyl)-1H-benzimidazol-1-yl]methyl}phenyl}-cyclohex-1-yl]carbonyl}-(4-fluorophenyl)glycinamide:

a) tert-Butyl(1R,2R)-2-(4-{[2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1H-benzimidazol-1-yl]methyl}phenyl)cyclohexane-1-carboxylate:

The 2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1H-benzimidazole fromExample 8A (22.01 g, 75.77 mmol) was added in portions to a suspensionof NaH (60% in mineral oil, 3.03 g, 75.77 mmol) in DMF (480 ml). After15 min at RT, the mixture was heated to 40° C., and stirring wascontinued for 30 min. After cooling to RT, the compound from Example 2A(25.5 g, 72.17 mmol) was added a little at a time, and the mixture wasstirred overnight 50 ml of water were added, the mixture was extractedwith diethyl ether and the organic phase was dried over sodium sulphateand chromatographed over silica gel (mobile phase: cyclohexane/ethylacetate=10:1 to 5:1), giving 38.86 g (95.7%) of a colourless solid. MS(ESI): 563.3 (M+H)⁺

¹H-NMR (DMSO-d₆): 0.00 (3H, s); 0.01 (3H, s); 0.85 (9H, s); 0.99 (9H,s); 1.3-2.0 (10H, m); 2.3-2.6 (2H, m); 2.87 (2H, t); 3.69 (2H, t); 5.41(2H, s); 6.95-7.18 (6H, m); 7.38-7.59 (2H, m)b) tert-Butyl(1R,2R)-2-(4-{[2-hydroxypropyl)-1H-benzimidazol-1-yl]-methyl}phenyl)cyclohexane-1-carboxylate:

I)

A solution of tetrabutylammonium fluoride (TBAF) in THF (1.1M, 68.9 ml,75.83 mmol) was added dropwise to a solution of the compound fromExample 17a (38.80 g, 68.93 mmol) in THF (750 ml), and the mixture wasstirred at RT for 30 min. The mixture was extracted with diethyl etherand the organic phase was dried over sodium sulphate and chromatographedover silica gel (mobile phase: dichloromethane/methanol=95:5), giving29.0 g (93.8%) of a colourless solid.

MS (EST): 449.5 (M+H)⁺

¹H-NMR (DMSO-d₆): 0.99 (9H, s); 1.25-1.55 (4H, m); 1.6-1.8 (3H, m);1.8-2.0 (3H, m); 2.3-2.65 (2H, m); 2.86 (2H, t); 3.49 (2H, q); 4.60 (1H,t); 5.42 (2H, s); 6.99 (2H, m); 7.08-7.18 (4H, m); 7.33-7.44 (1H, m);7.5-7.6 (1H, m).

II.)

The compound of Example 17b) can also be prepared by coupling2-(3-hydroxypropyl)-1H-benzimidazole directly to the compound fromExample 2A, analogously to the general procedure for alkylation A.

To this end, a 60% suspension of sodium hydride in mineral oil (880 mg,22 mmol) was initially charged in DMF (10 ml),2-(3-hydroxypropyl)-1H-benzimidazole (3.52 g, 20 mmol), dissolved in DMF(50 ml), was added, the mixture was stirred at RT for 10 min and thenheated at 40° C. for 30 min. After cooling to RT, the compound fromExample 2A (7.07 g, 20 mmol), dissolved in DMF (50 ml), was added, andthe reaction mixture was stirred at RT overnight. For work-up, themixture was shaken with water and ethyl acetate, the aqueous phase wasre-extracted twice with ethyl acetate and the combined organic phaseswere washed once with saturated sodium chloride solution. After dryingover sodium sulphate, the solvent was removed under reduced pressure andthe residue was crystallized by stirring with diethyl ether/petroleumether (5:1, 70 ml). The crystalline compound was filtered off and washedwith petroleum ether. Drying under reduced pressure gave 6.62 g (74% oftheory) of a colourless solid which, according to spectroscopiccharacterization, is identical to the compound of Example 17b) I.).c)(1R,2R)-2-(4-{[2-(3-Hydroxypropyl)-1H-benzimidazol-1-yl]methyl}phenyl)-cyclohexane-1carboxylic acid

Trifluoroacetic acid (212 ml) was added to an ice-cooled solution of thecompound from Example 17b) (26.5 g, 59.07 mmol) in dichloromethane (530ml), and the mixture was slowly warmed to room temperature and stirredat room temperature overnight. The reaction mixture was then madealkaline using 1N aqueous NaOH and washed with diethyl ether. Theaqueous phase was adjusted to pH 3-4 using 2N HCl (white turbidity) andextracted with methylene chloride. The organic phase was dried oversodium sulphate and the residue (white foam, 22.1 g, 95.3%) was thendried under oil pump vacuum and reacted directly, without furtherpurification.

MS (ESI): 393.1 (M+H)⁺

¹H-NMR (MeOH-d₄): 1.35-1.62 (4H, m); 1.75-1.90 (3H, m); 1.95-2.08 (3H,m); 2,52-2,60 (1H, m); 2,71-2,79 (1H, m); 3.25 (2H, t); 3.65 (2H, t);5.67 (2H, s), 7.15 (2H, d); 7.24 (2H, d); 7.46-7.55 (2H, m); 7.67 (1H,d); 7.75 (1H, d).d)(S)-N-{[(1R,2R)-2-{4-{[2-(3-Hydroxypropyl)-1H-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl]carbonyl}-(4-fluorophenyl)glycinamide

1-Hydroxybenzotriazole (6.95 g, 51.4 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC×HCl)(11.68 g, 60.95 mmol) were added to a solution of the compound fromExample 17c) (20.8 g, 53 mmol) in DMF (600 ml), and the mixture wasstirred at room temperature for 10 min.

N-methylmorpholine (29.14 ml, 265 mmol), (S)(4-fluorophenyl)glycinamidehydrochloride (see Example 9A c) and v)) (10.85 g, 53 mmol) and aspatula tip of dimethylaminopyridine (DMAP) were then added, and themixture was stirred at room temperature overnight. After addition ofwater (1.8 l), the mixture was stirred at room temperature for 2 h andthen with ice-cooling for 1 h. The title compound,(S)-N-{[(1R,2R)-2-{4-{[2-(3-hydroxypropyl)-1H-benzimidazol-1-yl]methyl}phenyl}-cyclohex-1-yl]carbonyl}-(4-fluorophenyl)glycinamide,was then filtered off and washed with water, n-hexane and diethyl ether.

Drying (3 days, 100 mbar, 45° C.) gave 25.5 g (85.7%) of a colourlesssolid.

MS (ESI): 543 (M+H)⁺

¹H-NMR (DMSO-d₄): 1.15-1.55 (4H, m); 1.55-2.0 (6H, m); 2.55-2.92 (4H,m); 3.48 (2H, q); 4.59 (1H, t); 5.15 (1H, d); 5.41 (2H, s); 6.856.98(6H, m); 7.05-7.17 (5H, m); 7.35-7.42 (1H, m); 7.53-7.66 (2H, m); 8.10(1H, d).

Instead of the (S)-(4-fluorophenyl)glycinamide hydrochloride, forexample from Example 9A c) or v), it is possible to employ the freeamine for the synthesis of the acid amide in question, with the sameresults.

EXAMPLE 18

(S)-N-{[(1R,2R)-2-{4-{[2-(hydroxymethyl)-1H-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl]carbonyl}-(4-fluorophenyl)glycinamide:

Starting with the compounds of Examples 2A, 6A and 9A c) or v), thetitle compound was prepared analogously to the process described inExample 17. Instead of removing the protective groups in two steps, thetert-butyldimethylsilyl ether and the tert-butyl ester of theintermediate analogous to Example 17 a) were removed in one step byaction of concentrated hydrochloric acid.

R_(f)(dichloromethane/methanol=10:1): 0.38

MS (ESI):515 (M+H)⁺

¹H-NMR (DMSO-d₄): 1.20-1.50 (4H, m); 1.61-1.78 (3H, m); 1.78-1.86 (1H,br. d); 2.65 (1H, br. t); 2.80 (1H, br. t); 4.71 (2H, br. d); 5.15 (1H,d); 5.48 (1H, d; AB-System); 5.53 (1H, d); 5.72 (1H, t); 6.87-6.94 (4H,m); 7.03-7.09 (2H, m); 7.09-7.19 (5H, m); 7.37 (1H, m); 7.58-7.65 (2H;m); 8.09 (1H, d).

EXAMPLE 19

(S)-N-{[(1R,2R)-2-{4-{[2-(2-hydroxyethyl)-1H-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl]carbonyl}-phenylglycinamide

Starting from 2(2-hydroxyethyl)-1H-benzimidazole, which was prepared bystandard processes, the title compound was prepared analogously to theprocess described for Example 17, using (S)phenylglycinamidehydrochloride instead of Example 9A c) or v).

R_(f)(dichloromethane/methanol=10:1): 0.27

MS (ESI): 511 (M+H)⁺

¹H-NMR (DMSO-d₄): 1.15-1.52 (4H, m); 1.59-1.91 (4H, m); 2.67 (1H, br.t); 2.83 (1H, br. t); 2.98 (2H, t); 3.86 (2H; br. q); 4.89 (1H, br. t);5.17 (1H, d); 5.44 (2H, br. s); 6.83-7.22 (12H, m); 7.38-7.48 (1H, m);7.54-7.67 (2H, m); 8.10 (1H, d).

EXAMPLE 20

(S)-N-{[(1R,2R)-2-{4-{[(2-Hydroxyethyl)-1H-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl]carbonyl}-(4-fluorophenyl)glycinamide:

The title compound was prepared analogously to Example 19, using(S)-(4-fluorophenyl)glycinamide hydrochloride from Example 9A c) or v).

R_(f)(dichloromethane/methanol 10:1): 0.26

MS (ESI): 529 (M+H)⁺

¹H-NMR (DMSO-d₆): 1.19-1.51 (4H, m); 1.61-1.78 (3H, m); 1.78-1.87 (1H,br. d); 2.65 (1H, br. t); 2.80 (1H, br. t); 2.97 (2H, t); 3.85 (2H, q);4.85 (1H, t); 5.15 (1H, d); 5.44 (2H, br. s); 6.85-6.99 (6H, m);7.08-7.19 (5H, m); 7.40 (1H, pseudo-d); 7.57 (1H, pseudo-d); 7.61 (1H,br. s); 8.10 (1H, d).

EXAMPLE 21

(S)-N-{[(1R,2R)-2-{4-{[2-(3-Hydroxypropyl)-1H-benzimidazol-1-yl]methyl}-phenyl}-cyclohex-1-yl]carbonyl}-(3-pyridyl)glycinamide:

N-methylmorpholine (0.13 mL 1.2 mmol) was added to a solution of thesubstance from Example 17 c) (118 mg, 0.3 mmol), 1-hydroxybenzotriazole(40.5 mg, 0.3 mmol), EDC hydrochloride (69 mg, 0.36 mmol) and4(N,N-dimethylamino) pyridine (DMAP, 1 mg) in DMF (3 ml), and theresulting mixture was transferred into a reaction vessel containing(S)(3-pyridyl)glycinamide hydrochloride (101 mg, 0.45 mg)—which can beprepared analogously to the substance from Example 9A c) or v). Thereaction mixture was reacted at room temperature for three days and thenpurified directly by preparative high-pressure chromatography onreversed-phase silica gel (Grom-Sil 120 ODS-4 HE 5 μm) usingwater/acetonitrile (gradient: 10:90 to 90:10). The resulting solutionwas freed of acetonitrile under reduced pressure, frozen in a dry-icebath and freeze-dried overnight. This gave 143 mg (91% of theory) of acolourless lyophilisate.

R_(f)(dichloromethane/methanol=10:1): 0.11

MS(ESI): 526 (M+H)

¹H-NMR (DMSO-d₆): 1.15-1.55 (4 H, m); 1.57-1.91 (4 H, m); 1.97 (2 H,quint.); 2.65 (1 H, br. t); 2.81 (1 H, br. t); 3.27 (2 H, t); 3.52 (2 H,t); 5.29 (1 H, d); 5.69 (2 H, s); 7.07-7.20 (4 H, m); 7.20-729 (1 H, m);7.32 (1 H, br. s); 7.38-7.45 (1 H, m); 7.46-7.60 (2 H, m); 7.72-7.87 (3H; m); 8.09 (1 H, br. s); 8.36 (1 h, d); 8.44 (1 H, m).

1. A compound of the formula (I)

in which A, D, E and G each represents CH, L¹ and L² are identical ordifferent and independently of one another each represents one or moreradicals selected from the group consisting of hydrogen, halogen,hydroxyl, carboxyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and (C₁-C₆)-alkoxycarbonyl, R¹ representsa radical of the formula CO—NR⁴R⁵, in which R⁴ and R⁵ are identical ordifferent and each represents hydrogen or (C₆-C₆)-alkyl, R² represents

 in which R⁷ represents hydrogen, (C₁-C₆)-alkyl, hydroxy-(C₁-C₆)-alkylor (C₃-C₇)-cycloalkyl and the piperazinyl group is optionallysubstituted by one to three hydroxyl groups and/or by a radical of theformula —NR⁸R⁹ in which R⁸ and R⁹ are identical or different and eachrepresents hydrogen, (C₁-C₆)-alkyl, or (C₃-C₇)-cycloalkyl, and R³represents a phenyl or naphthyl group where the rings are optionallymono- or polysubstituted by at least one radical selected from the groupconsisting of halogen, hydroxyl, carboxyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy and(C₁-C₆)-alkoxycarboxyl, or an enantiomer diastereomer, salt, hydrate orprodrug thereof.
 2. The compound according to claim 1 where A, D, E andG each represents the CH group, L₁ and L₂ are identical or different andindependently of one another each represents one or more radicalsselected from the group consisting of hydrogen, fluorine, chlorine,cyano, trifluoromethyl and trifluoromethoxy, R¹ represents a radical ofthe formula HO—NR⁴R⁵, in which R⁴ and R⁵ are identical or different andeach represents hydrogen or (C₁-C₃)-alkyl, R² represents

 in which R⁷ represents hydrogen, (C₁-C₄)-alkyl, hydroxy-(C₁-C₄)-alkylor (C₃-C₆)-cycloalkyl and the piperazinyl group is optionallysubstituted by one hydroxyl group and/or by a radical of the formula—NR⁸R⁹, in which R⁸ and R⁹ are identical or different and eachrepresents hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl, and R³represents a phenyl group which is optionally mono or polysubstituted byat least one radical selected from the group consisting of fluorine,chlorine, cyano, trifluoromethyl and trifluoromethoxy, or an enantiomer,diastereomer, salt, hydrate or prodrug thereof.
 3. The compoundaccording to claim 1 or 2 where A, D and E each represent the CH group,G represents the CH group, L¹ and L² each represent hydrogen, R¹represents a radical of the formula —CO—NR⁴R⁵, in which R⁴ and R⁵ eachrepresent hydrogen, R² represents a 4-R⁷-piperazin-1-yl radical, inwhich R⁷ represents hydrogen, (C₁-C₄)-alkyl or (C₃-C₆)-cycloalkyl, andR³ represents a phenyl radical which may optionally be mono- orpolysubstituted by fluorine, or an enantiomer, diastereomer, salt,hydrate or prodrug thereof.
 4. The compound according to claim 1 wherethe radical R¹ represents a radical of the formula CO—NR⁴R⁵ where R⁴ andR⁵ are hydrogen and the other radicals are as defined in claim
 1. 5.Compounds according to claim 1, characterized by the followingstereochemistry according to formula (Ia):

where the substituents R¹, R², R³, L¹ and L² and the radicals A, D, Eand G are each as defined in claim
 1. 6. A process for preparingcompounds of the formula (I) according to claim 1, characterized in that(A) a compound of the general formula (II)

in which L² is as defined above in claim 1, T represents (C₁-C₄)-alkyl,and V represents a suitable leaving group, is initially converted byreaction with a compound of the general formula (III)

in which A, D, E, G, and L¹ are each as defined above in claim 1 and R¹¹has the meaning of R² given above in claim 1, where amino and hydroxylfunctions are optionally blocked by suitable amino- orhydroxyl-protective groups, in an inert solvent, depending on thedefinition of R¹¹ optionally in the presence of a base, into the acompound of the general formula (IV)

in which R¹¹, A, D, E, G, L¹, L² are each as defined above in claim 1and T is as defined above, which is converted in a subsequent step usingacid or base into the corresponding carboxylic acid of the generalformula (V)

in which R¹¹, A, D, E, G, L¹, L² are each as defined above in claim 1,which is, if appropriate, activated, by conversion into a correspondingcarboxylic acid derivative, and which is subsequently reacted with acompound of the general formula (VI) or salt thereof

in which R¹ and R³ are each as defined above in claim 1 in an inertsolvent, and, if R¹¹ carries one of the abovementioned protectivegroups, this is optionally removed by customary methods either in thehydrolysis to the acids (IV)→(V) or after the reaction with thecompounds of the general formula (VI), or (B) if R² represents asaturated heterocycle which is attached directly to the imidazole ringvia a nitrogen atom, the above mentioned compound of the general formula(II) is initially converted with a compound of the general formula(IIIa)

in which A, D, E, G and L¹ are each as defined above in claim 1 and Yrepresents halogen or mesylate, in an inert solvent into thecorresponding compound of the formula (VII)

in which Y, A, D, E, G, L¹, L² are each as defined above in claim 1 andT is as defined above, which is reacted in a subsequent step with acompound of the general formula (VIII)HNR¹²R³  (VIII) in which R¹² and R¹³ together with the nitrogen atomform a heterocycle according to the definition of R² given in claim 1 togive a compound of the general formula (IX)

in which A, D, E, G, L¹, and L², are each as defined above in claim 1and R¹², R¹³ and T are as defined above, which is in the subsequentsteps, converted as described under (A) by hydrolysis into thecorresponding carboxylic acid of the general formula (X)

in which A, D, E, G, L¹, and L², are each as defined above in claim 1and R¹² and R¹³ are as defined above and this compound is finallyreacted with the a compound of the general formula (VI) according toknown methods for preparing amides from carboxylic acids and amines andconverted into the compound of the general formula (I) where thecompound of the general formula (I) obtained according to processvariant (A) or (B) can, if appropriate, subsequently be converted intothe corresponding salts.
 7. A pharmaceutical composition comprising acompound of the formula (I) according to claim 1 in admixture with atleast one pharmaceutically acceptable, essentially non-toxic carrier orexcipient.
 8. Compounds according to claim 2 where the radical R¹represents a radical of the formula CO—NR⁴R⁵ where R⁴ and R⁵ arehydrogen and the other radicals are as defined in claim
 2. 9. Compoundsaccording to claim 2, with the following stereochemistry according toformula (Ia):

where the substituents R¹, R², R³, L¹ and L² and the radicals A, D, Eand G are each as defined in claim
 2. 10. Compounds according to claim3, with the following stereochemistry according to formula (Ia):

where the substituents R¹, R², R³, L¹ and L² and the radicals A, D, Eand G are each as defined in claim
 3. 11. Compounds according to claim4, with the following stereochemistry according to formula (Ia):

where the substituents R¹, R², R³, L¹ and L² and the radicals A, D, Eand G are each as defined in claim
 4. 12. The process of claim 6 whereinT represents methyl or tert-butyl.
 13. The process of claim 6 wherein Vrepresents halogen, mesylate, or tosylate.
 14. The process of claim 13wherein V represents bromine.
 15. The process of claim 6 wherein saidcarboxylic acid derivative of a compound of formula V is a carbonylhalide, carboxylic anhydride or carboxylic ester.
 16. The process ofclaim 6 wherein Y of formula IIIa is chlorine or bromine.
 17. Theprocess of claim 6 wherein the steps of converting the compounds ofgeneral formula I into the corresponding salts, as provided in the finalparagraph of claim 6, is carried out by reaction with an acid.
 18. Apharmaceutical composition comprising a compound of the formula (I)according to claim 2 in admixture with at least one pharmaceuticallyacceptable, essentially non-toxic carrier or excipient.
 19. Apharmaceutical composition comprising a compound of the formula (I)according to claim 3 in admixture with at least one pharmaceuticallyacceptable, essentially non-toxic carrier or excipient.
 20. Apharmaceutical composition comprising a compound of the formula (I)according to claim 4 in admixture with at least one pharmaceuticallyacceptable, essentially non-toxic carrier or excipient.
 21. Apharmaceutical composition comprising a compound of the formula (I)according to claim 5 in admixture with at least one pharmaceuticallyacceptable, essentially non-toxic carrier or excipient.